Although American-style football (ASF) remains the most popular team sport among American youths, research has demonstrated a high prevalence of hypertension and evidence of sub-clinical arterial stiffening in collegiate ASF participants. Of concern to public health is the recent finding of increased cardiovascular mortality in retired professional ASF linemen compared to the general population. For ultra-endurance athletes, recent data suggest the possibility that long-term and excessive endurance exercise may lead to the development of an exercise-induced right ventricular cardiomyopathy. However, more definitive insights to these observations, including detailing the mechanisms underlying ASF-induced vascular dysfunction, are lacking. This research will use a comprehensive array of cardiac imaging, vascular function testing, and high- resolution, liquid chromatography-mass spectrometry metabolomics to fully characterize the impact of ASF participation versus endurance exercise on cardiovascular structure and function and metabolism in a large cohort of high school and collegiate ASF athletes. The scientific goals of this research are to: 1) provide insight into the mechanisms and pathophysiology of ASF-induced vascular dysfunction; and 2) generate novel characterization of metabolic phenotypic adaptations present in sport-specific athletic training regimens. The working hypotheses of this project are: 1) ASF-induced arterial stiffness begins during high school ASF participation and predicts increased left ventricular hypertrophy (LVH) and reduced tissue-Doppler derived diastolic parameters in ASF participants, 2) ASF participants and endurance athletes will demonstrate distinct metabolic profiles that will be associated with specific clinical characteristics and cardiovascular phenotypic patterns, and 3) mechanisms underlying ASF-induced vascular dysfunction are multi-factorial and include oxidative stress, undiagnosed and untreated obstructive sleep apnea, and over-used non-steroidal anti- inflammatory medications. Aim 1 will address the temporal change in metrics of arterial stiffness associated with ASF participation and the relationships of changes in vascular function with cardiac structural and functional adaptations in post-season ASF participants. Aim 2 will investigate changes in the metabolic profile of ASF participants and endurance athletes and the relationships of changes in the metabolic phenotype of these athletes with changes in cardiac structure and function, clinical characteristics, and vascular function. Aim 3 is an exploratory aim that will investigate possible mechanisms responsible for the development of ASF- induced hypertension and vascular dysfunction including weight gain, oxidative stress, obstructive sleep apnea, and overused non-steroidal anti-inflammatory medications. For this K23 Mentored Career Development Award, I will gain new mentored research and training from a multidisciplinary team of expert mentors (Drs. Arshed A. Quyyumi, Aaron L. Baggish, Dean P. Jones, and Laurence S. Sperling). The primary goal of the career development plan is to develop expertise in clinical research (Master of Science), advanced imaging techniques, vascular function testing, and high-resolution metabolomics for use in future clinically oriented sports cardiology research. This will complement my sports cardiology training to-date and distinguish my career moving forward. The proposed research, in combination with the structured mentoring and training plan will facilitate my long-term goal of developing an independently funded clinical and translational sports cardiology research program consistent with the mission of the NHLBI.